ABSTRACT: PROJECT 3: Tumor-associated biomarkers for HIV-associated Diffuse Large B-cell Lymphoma in Malawi and South Africa Lymphoma incidence in sub-Saharan Africa (SSA) is increasing due to epidemic levels of HIV infection, population growth, and aging. Diffuse large B-cell lymphoma (DLBCL) is highly associated with HIV, the commonest lymphoma subtype among HIV-infected individuals, and the commonest cause of cancer death among people living with HIV in high-income countries (HIC). Despite histologically similar appearances, HIV- associated DLBCL differs biologically from DLBCL in immunocompetent populations and may also differ within HIV-infected populations depending on the HIV immunologic and virologic environment in which they occur. However, current diagnosis, risk stratification and therapy do not account for these differences which remain incompletely understood, and suitable patient cohorts to overcome these challenges have historically been lacking. Our long-term goal is to improve outcomes for HIV-associated DLBCL in SSA by applying promising regionally generated biomarkers, building on our previous immunophenotypic and molecular analyses of DLBCL from the region, to a prospective cohort of patients in Malawi and South Africa. The work will further characterize tumor microenvironmental factors that influence tumor biology across the spectrum of HIV- associated immune dysfunction. We hypothesize that prognostic biomarkers can be identified and implemented in SSA to better tailor treatment for this challenging and vulnerable population. Given the generalized HIV epidemic in the region, comparisons within specific tumor types based on HIV status are uniquely possible in this setting. Similar studies are challenging to conduct in the US, given relatively few HIV- positive cancers, and differences between the HIV-infected and general HIV-negative US population with respect to age, as well as behavioral and other cancer risk factors. These efforts will be enhanced by established collaborations with bioinformatics and sequencing core facilities, allowing the proposed research to yield insights which inform the care of HIV-associated DLBCL worldwide. The proposed work is necessary to understand the biological factors underlying lymphomagenesis and improve survival for HIV-associated DLBCL in high- and low-income countries.